Numerous drugs are prepared in the form of suspensions for ophthalmic, oral, otic, nasal and respiratory topical applications. Formulation of pharmaceutical dosages of water-insoluble drugs as suspensions is frequently hampered by the subsequent formation of cakes resulting from aggregation of the suspended material. Polymeric compounds (e.g. polyvinyl pyrrolidone ("PVP"), polyvinyl alcohol ("PVA"), and dextran are commonly used to stabilize such suspensions. An alternative approach to the preparation of such drugs is to enhance the solubility of the drugs within the formulation by vehicles such as emulsions, liposomes, and cyclodextrins. However, certain drugs, in their therapeutic concentrations, are not sufficiently stabilized or solubilized by these methods for the above-mentioned applications.
Generally, a variety of cyclodextrins have been used to solubilize poorly water-soluble or water-insoluble drugs and to stabilize drugs which are unstable in water in the form of inclusion complexes. The present invention relates to the entirely novel use of modified cyclodextrins to stabilize and facilitate the formation of aqueous suspensions of particulate water-insoluble drugs.
Cyclodextrins are cyclic oligosaccharides. The most common cyclodextrins are .alpha.-cyclodextrin, which is composed of a ring of six glucose residues; .beta.-cyclodextrin, which is composed of a ring of seven glucose residues; and .gamma.-cyclodextrin, which is composed of a ring of eight glucose units. The inside cavity of a cyclodextrin is lipophilic, while the outside of the cyclodextrin is hydrophilic; this combination of properties has led to widespread study of natural cyclodextrins, particularly in connection with pharmaceuticals, and many inclusion complexes have been reported. .beta.-Cyclodextrin has been of special interest because of its cavity size, but its relatively low aqueous solubility (about 1.8% w/v at 25.degree. C.) and attendant nephrotoxicity have limited its use in the pharmaceutical field.
Attempts to modify the properties of natural cyclodextrins have resulted in the development of heptakis (2,6-di-O-methyl)-.beta.-cyclodextrin, heptakis (2,3,6-tri-O-methyl)-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, .beta.-cyclodextrin-epichlorohydrin polymer and others. For a comprehensive review of cyclodextrins and their use in pharmaceutical research, see Pitha et al, in Controlled Drug Delivery, ed. S. D. Bruck, Vol. I, CRC Press, Boca Raton, Fla., pp. 125-148 (1983). For an even more recent overview, see Uekama et al, in CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3(1), 1-40 (1987); Uekama, in Topics in Pharmaceutical Sciences 1987; Uekama, in Topics in Pharmaceutical Sciences 1987, eds. D. D. Breimer and P. Speiser, Elsevier Science Publishers B. V. (Biomedical Division), 1987, 181-194 and Pagington, Chemistry in Britain May 1987; pp. 455-458.
Inclusion complexes of .alpha.-, .beta.- or .gamma.-cyclodextrin or their mixtures with a variety of drugs have been described by numerous parties and various advantages have been attributed to the complexes. See U.S. Pat. Nos. 4,024,223; 4,228,160; 4,232,009; 4,351,846; 4,352,793; 4,383,992; 4,407,795; and 4,424,209.
Topical steroids such as corticosteroids are commonly used for anti-inflammatory therapy of the eye, especially for treating inflammatory conditions of the palpebral or bulbar conjunctiva, cornea and anterior segment of the globe. Common therapeutic applications for steroids include allergic-conjunctivitis, acne rosacea, superficial punctate keratitis and iritis cyclitis. Steroids also are used to ameliorate inflammation associated with corneal injury due to, chemical or thermal burns, or penetration of foreign bodies. Such conditions may result from surgery, injury, allergy or infection to the eye and can cause severe discomfort.
Despite their therapeutic advantages, topical ocular use of corticosteroids is associated with a number of complications, including posterior subcapsular cataract formation, elevation of intraocular pressure, secondary ocular infection, retardation of corneal wound healing, uveitis, mydriasis, transient ocular discomfort and ptosis. Numerous systemic complications also may arise from the topical ocular application of corticosteroids. These complications include adrenal insufficiency, Cushing's syndrome, peptic ulceration, osteoporosis, hypertension, muscle weakness or atrophy, inhibition of growth, diabetes, activation of infection, mood changes and delayed wound healing.
Topical steroids for treating ocular inflammations can be based on soft drugs. Soft drugs, as are known in the art, are designed to provide maximal therapeutic effect and minimal side effects. By one approach, synthesis of a "soft drug" can be achieved by structurally modifying a known inactive metabolite of a known active drug to produce an active metabolite that undergoes a predictable one-step transformation in-vivo back to the inactive metabolite. (See U.S. Pat. Nos. 4,996,335 and 4,710,495 for "soft" steroids). "Soft drugs" therefore are biologically active chemical components characterized by predictable in vivo metabolism to non-toxic derivatives after they provide their therapeutic effect.
Pharmaceutical compositions of water-insoluble drugs such as corticosteroids in aqueous suspensions for ocular and other uses must satisfy constraints imposed by physiological compatibilities such as pH, osmolality, and particle size of the suspended steroids. Furthermore, these compositions must meet requirements for preservative efficiency and ease of suspension over extended periods of time.
Therapeutic suspensions of corticosteroids typically employ polymeric compounds such as PVP and PVA as suspending agents in concentrations ranging from 0.1 to 10%. See U.S. Pat. No. 2,861,920. Polymeric compounds such as PVP, PVA, sodium carboxymethylcellulose, dextran, and surface-active agents such as Polysorbate 80, Polysorbate 20, and tyloxapol also have been used to stabilize corticosteroid suspensions intended for ophthalmic, nasal, and otic uses.
The amounts of polymeric compounds and surface active agents employed to provide stability to these suspensions must accurately be determined. For example, an excessive amount of polymeric compound may hamper the antimicrobial effects of preservatives added to the suspension. Also, pharmaceutical ocular and nasal dosages of these suspensions either must be buffered or have a pH with no buffering capacity. These suspensions also should be isotonic.
Formulation of aqueous suspensions of corticosteroids for ocular applications and other uses has been hampered by agglomeration of the steroid particles. Agglomeration particularly has been a problem for "soft" steroids such as loteprednol etabonate ("LE"), bechmethasone, betamethasone, fluocinolone, fluoromethalone, prednisolone, either alone or in combination with other therapeutic drugs such as betaxalol, athenolol, livobanolol, epinenephrin, dipivalyl, oxonolol, acetazilumide-base, methazalomide, tobramycin, gentamycin, piroxicam, indomethacine, naproxen, phenylbutazone, ibuprofen, diclofenac-acid.
LE is a soft corticoseroid that has ocular anti-inflammatory activity. This corticosteroid is based on a known inactive metabolite of the active drug prednisolone. LE is an analog of prednisolone that does not have a 20-keto group attached to the 17.beta.-position. Instead, the 17-.beta. position is occupied with a metabolically-labile ester function. In biological systems, LE is hydrolysed to the inactive carboxylic acid metabolite (PJ-91) that does not bind to glucocorticoid receptors. LE also provides superior safety by reducing the risk of steroid induced cataracts and elevation of intra-ocular pressure. The lability of LE to enzymes located in the blood and/or liver also reduces the likelihood of systemic side effects.
Soft steroids such as corticosteroids have the potential for treating inflammation without inducing elevation of intraocular pressure. In addition, these steroids lessen the tendency to induce cataracts which may result from interaction of the corticosteroids with the ocular lens proteins.
LE provides therapeutic advantages over other corticosteroids by providing efficacy similar to its parent compound, namely, prednisolone acetate. Stable aqueous suspensions of LE, however, cannot be obtained by accepted buffering systems or ionic tonicity agents. Surprisingly, common tonicity agents such as aqueous solutions containing 0.9% NaCl, 10% EDTA, or phosphate buffer, even in concentrations as low as 1 mM therefore can not be employed in aqueous suspensions of corticosteroids such as LE.
A need therefore exists for aqueous suspensions which have therapeutically effective amounts of "soft" drugs such as corticosteroids, but which avoid the problems of agglomeration associated with the suspensions of the prior art.